Automated pipette machine

ABSTRACT

A pipette nozzle is provided for use on a movable arm on an automated pipette machine. The pipette nozzle includes a body defining a passage therethrough and having at least two seating surfaces provided on the body. The first seating surface is configured to receive and sealingly mate with a first size of pipette tip in a manner such that the first end of the passage is in fluid communication with the first size of pipette tip. The second seating surface is configured to correspondingly receive, sealingly mate and provide passage first end fluid communication with a second size of pipette tip. There is also provided an automated pipette machine which includes a tip ejector system including an arm that is movable between a first position and a second position wherein in the first position the arm is positioned to engage the tip during movement of the nozzle along a selected path and to prevent movement of the tip along the selected path while permitting the nozzle to move along the selected path, so that the movement of the nozzle along the selected path causes the nozzle and the tip to disengage from each other, and wherein in the second position the arm is positioned to avoid engagement with the tip during movement of the nozzle.

This application is a division of co-pending U.S. application Ser. No.11/182,741 filed on Jul. 18, 2005, which in turn is a Parent, whichclaims the benefit of U.S. Provisional Application No. 60/588,331 filedon Jul. 16, 2004. The entire disclosure of the prior application ishereby incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

This invention relates generally to automated apparatus for handlingchemical and biological fluids, and more particularly to automaticpipette machines.

BACKGROUND OF THE INVENTION

Automatic pipette machines or robots are used in the chemical andbiological fields to automatically pipette fluids from one place toanother, without the need for direct human involvement. Generally,automated pipette robots have three axes of motion to allow a moveabletip head to access different containers with fluid samples in a givenarea. One class of robots are known as θ-z-θ robots which combinerotational (θ) and vertical (z) motion of a robot arm holding the tiphead with rotational (θ) motion of a carousel that holds the samples,thereby allowing the tip head to access the samples on the carousel. Amore common class of robots are x-y-z gantry style robots (e.g. BioMekFX™, Qiagen™ Biorobots™) where the moveable tip head moves along onevertical axis and two orthogonal horizontal axes of motion. To avoidcontamination, many automatic pipette machines use disposable pipettetips. Typically, the tip head on these robots has one or more nozzlesthat receive a pipette tip.

Typically, the tip heads on the automated pipette robots can accommodateonly one size of disposable pipette tip. However, a given size ofpipette tip is best suited for pipetting a limited range of volumes offluid. Some processes require that a wider range of volumes of fluid betransferred from one place to another than can be accommodated by thetip. In such instances, either the pipette head must make multiple tripsbetween the source and destination locations in order to cumulativelytransfer the required volume, or human intervention is required totransfer the volumes that cannot be effectively handled by the pipettemachine. It would be desirable to provide an automated pipette machinecapable of pipetting a wider range of volumes.

Automated pipette systems often use a hydraulic fluid in the fluid linesthat connect the pump to the pipette tip head because hydraulic fluidsare less compressible than air. As the liquid volume in the pipette tipincreases, the pressure drop between the pump and the tip headincreases. It is easier to calibrate the pump to attain the desiredpipette volume accuracy if most of the volume in the line between thepump and the tip head is a hydraulic fluid. In addition, for positivedisplacement pumps, the volume of liquid the pump can draw into the tipwith a single piston stroke is higher using a hydraulic fluid.

Existing automated pipette technology is limited to aspirating a maximumof approximately 1 mL of liquid. In these machines, there is tubing of arelatively small diameter and of sufficient length between the tip headand the pump to accommodate up to 1 mL of air displaced from the pipettetip during aspiration. Small diameter tubing is used so that if there isan interface between hydraulic fluid and air in a section of the tubingthat is not horizontal, the hydraulic fluid does not flow down into theair volume. If this occurs, then air can be inadvertently introducedinto the pump, causing a loss of volumetric dispensing accuracy. Manyanalysis processes require that volumes significantly greater than 1 mLbe pipetted. To pipette larger volumes of fluid a longer tube can beused while maintaining the diameter of the tube constant so that thetube remains small enough in cross-section so that no air isinadvertently introduced into the pump during operation.

A longer tube, however, has several drawbacks associated with it. Forexample, in a long length of tubing there is an increased chance that asthe hydraulic fluid is drawn into the pump, there will be breaks at theair-hydraulic fluid interface resulting in the formation of discretebubbles between the main interface and the nozzle. When the pumpinitiates the dispensing step, these bubbles will be ahead of the maininterface and may be expelled from the nozzle, contaminating the tip andpotentially contaminating the fluid that the tip aspirated, and thefluid volume into which the tip is dispensing. Additionally, a longlength of tubing provides increased pressure drop at a given fluidflow-rate, which in turn, means that pump cavitation would occur at arelatively lower flow-rate during aspiration. Furthermore, the increasedpressure drop reduces the maximum dispensing flow-rate. Another drawbackis that, for both the aspirating and dispensing steps, the higherpressure drop through a long length of tubing may increase the chance ofleakage at connections between the different tubes, the pump, and thenozzle, since higher (or lower) initial pressures are required at thepump to achieve operation.

These drawbacks associated with longer tubing as described above alsoapply to the use of small diameter tubing for 1 ml machines that arecurrently in use. In other words, for any machine that incorporates alength of relatively small diameter tubing which functions as areservoir for air during operation, the above described problems arepresent.

It would be desirable to have a system that can transfer volumes offluid without incorporating long hydraulic fluid lines.

Another drawback related to current automated pipette machines relatesto the disposal of used pipette tips. There are currently variousmechanisms proposed and in use for removing disposable pipette tips fromthe pipette nozzle. However, many of these mechanisms are relativelyintricate, thereby increasing the complexity of the pipette machines andthe cost of manufacture. Furthermore, many of the devices of the priorart eject the pipette tip in an uncontrolled manner, usually into adisposal bin, thereby making it impractical to reuse the tip if desired.For example, in some analysis techniques, the same material istransferred in non-consecutive steps, in which case reuse of the tip isdesirable since contamination is not an issue. It would be desirable tohave a pipette machine that is capable of reusing a pipette tip.

SUMMARY OF THE INVENTION

In a first aspect, the invention is directed to a pipette nozzle for useon a movable arm on an automated pipette machine. The pipette nozzleincludes a body defining a passage therethrough. The pipette nozzleincludes a connecting portion on the body for connecting the pipettenozzle to the movable arm. There are provided at least two seatingsurfaces on the body, including a first seating surface and a secondseating surface. The first seating surface is configured to receive andsealingly mate with a first size of pipette tip in a manner such thatthe passage is in fluid communication with the first size of pipettetip. The second seating surface is configured to receive and sealinglymate with a second size of pipette tip in a manner such that the passageis in fluid communication with the second size of pipette tip.

In a second aspect, the invention is directed to an apparatus for use onan automated pipette machine for transmitting pressure changes producedby a pump on the machine to a pipette nozzle. The apparatus includes ahousing defining a chamber. The apparatus further includes a firstconduit extending into the chamber and having a first opening positionedin the chamber. The first conduit is fluidically connectible to thenozzle. The apparatus further includes a second conduit extending intothe chamber and having a first opening positioned in the chamber,wherein the second conduit is fluidically connectible to the pump. Thefirst opening of the first conduit is positioned above the first openingof the second conduit. The chamber defines at least a selected volumebetween the height of the first opening of the first conduit and theheight of the first opening of the second conduit.

In a third aspect, the invention is directed to a tip ejector system foruse on an automated pipette machine to eject a pipette tip from apipette nozzle on the machine. The tip ejector system includes an armthat is movable between a first position and a second position. In thefirst position the arm is positioned to engage the tip during movementof the nozzle along a selected path thereby preventing movement of thetip along the selected path while permitting the nozzle to move alongthe selected path, so that the movement of the nozzle along the selectedpath causes the nozzle and the tip to disengage from each other. In thesecond position the arm is positioned to avoid engagement with the tipduring movement of the nozzle.

In a fourth aspect, the invention is directed to an automated pipettemachine including a movable carousel having a plurality of pipettereceptacles, a movable pipette machine arm with a pipette nozzleattached thereto, and a tip ejector system. The pipette nozzle includesa body defining a passage therethrough and at least two seating surfaceson the body, including a first seating surface and a second seatingsurface. The first seating surface is configured to receive andsealingly mate with a first size of pipette tip in a manner such thatthe passage is in fluid communication with the first size of pipettetip. The second seating surface is configured to receive and sealinglymate with a second size of pipette tip in a manner such that the passageis in fluid communication with the second size of pipette tip. The tipejector system includes a tip ejector arm that is movable between afirst position and a second position, wherein in the first position thetip ejector arm is positioned to engage the tip during movement of thenozzle along a selected path and to prevent movement of the tip alongthe selected path while permitting the nozzle to move along the selectedpath, so that the movement of the nozzle along the selected path causesthe nozzle and the tip to disengage from each other, and wherein in thesecond position the tip ejector arm is positioned to avoid engagementwith the tip during movement of the nozzle.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the present invention and to show moreclearly how it may be carried into effect, reference will now be made byway of example to the accompanying drawings, in which:

FIG. 1 is perspective view of an automated pipette machine in accordancewith an embodiment of the present invention;

FIG. 2 is a side view of a pipette arm of the machine in FIG. 1;

FIG. 3 is a side view of a nozzle of the pipette arm in FIG. 2;

FIG. 4 is a cross-sectional view along section line 4-4 shown in FIG. 3;

FIG. 5 is a side view of the nozzle shown in FIG. 1, with a firstpipette tip mounted thereon;

FIG. 6 is a side view of the nozzle shown in FIG. 1, with a secondpipette tip mounted thereon;

FIG. 7 is a longitudinal cross section of the pipette arm of FIG. 2;

FIG. 8 is a side view of a reservoir apparatus of the pipette arm ofFIG. 7;

FIG. 9 is a cross-sectional view along section line 9-9 shown in FIG. 8;

FIGS. 10 a and 10 b are schematic diagrams of the reservoir apparatus ofFIG. 8;

FIG. 11 is an elevation view of components of the pipette machine ofFIG. 1, which are involved in the ejection of a disposable pipette tipfrom the nozzle;

FIGS. 12 a, 12 b, 12 c and 12 d are a series of elevation viewsillustrating tip ejection of a first pipette tip from the pipette nozzleshown in FIG. 1;

FIGS. 13 a, 13 b, 13 c and 13 d are a series of elevation viewsillustrating tip ejection of a second pipette tip from the pipettenozzle shown in FIG. 1;

FIGS. 14 a and 14 b are plan views of an ejector arm in alignment withtip compartments on a carousel on the pipette machine of FIG. 1; and

FIG. 15 is a side view of an alternative pipette arm for use with themachine in FIG. 1.

DETAILED DESCRIPTION OF THE DRAWINGS

In the accompanying drawings, like numerals indicate the same elements.It will be understood that the present disclosure is an exemplificationof the principles of the invention and does not limit the invention tothe illustrated embodiments. Therefore, specific details disclosedherein are not to be interpreted as limiting, but rather as a basis forthe claims and as a representative basis for teaching one skilled in theart to employ the present invention.

Referring to FIG. 1, there is illustrated an automated pipette machine10, which may also be referred to as an automated pipette robot 10, inaccordance with an embodiment of the present invention. The automatedpipette machine 10 has a moveable arm 12 and a carousel 14. The carousel14 has a plurality of apertures 16 of varying size and shape forreceiving sample or reagent containers 17, or one or more carriers 18which are themselves configured to support sample or reagent containers17. Containers 17 that may be carried by the carriers 18 include, forexample, test tubes, vials and the like. Disposable pipette tips 23 mayalso be provided on the carousel 14 and may be held in one or morecarriers 19.

Referring to FIG. 2, arm 12 includes a pipette head 20 upon which ismounted a nozzle 22 for holding a disposable pipette tip 23. Referringto FIG. 1, the machine 10 may move arm 12 and/or carousel 14 in any wayknown in the art to provide access by the arm 12 to fluid held in thecontainers 17 on the carousel 14. For example, the pipette machine 10may be a θ-z-θ robot where the rotational (θ) and vertical (z) motion ofthe arm 12 is combined with rotational (θ) motion of the carousel 14 toprovide access by the arm 12 to containers 17 on the carousel 14 and todispose the pipette tip 23 in carrier 19 or the carousel 14.Alternatively, the automated pipette machine 10 may, for example, be anx-y-z gantry style machine having an arm that is movable along threeorthogonal axes, eg. a vertical axis and two orthogonal horizontal axes.An alternative configuration of the arm 12 is shown in FIG. 15.

Reference is made to FIGS. 3 and 4, which show the pipette nozzle 22.The tip nozzle 22 may connect to the pipette head 20 in any suitableway. For example, the nozzle 22 may include a connecting portion 24 at afirst end 26. The connecting portion 24 may, for example, include a bore42 (FIG. 4), for connecting by press-fit to a corresponding externalsurface on the pipette head 20.

Reference is made to FIGS. 5 and 6. The nozzle 22 may be sized to holdone or more different sizes of pipette tip 23. For example, the nozzle22 may be sized to hold a first pipette tip 25 as shown in FIG. 5, and asecond pipette tip 27 as shown in FIG. 6. The first tip 25 may have alarger internal volume than the second tip 27, and may thus be sized forholding a relatively greater quantity of fluid than the second tip 27.The first tip 25 has a nozzle-mating end 38, which may have a largerinternal cross-section than a nozzle-mating end 39 for the second tip27. The nozzle-mating ends 38 and 39 of the tips 25 and 27 may beslightly tapered.

The nozzle 22 has a first seating surface 30 and a second seatingsurface 32, which are configured for receiving the first and seconddisposable pipette tips 25 and 27 respectively. The first seatingsurface 30 may be adjacent to the cylindrical portion 24. The secondseating surface 32 is sized for receiving the smaller tips 27. Thesecond sealing surface 32 is positioned closer to the end 37 than is thefirst sealing surface 30. A tapered shoulder 34 separates the first andsecond seating surfaces 30 and 32. A terminal taper portion 36 ispositioned at the distal or remote end 37 of the nozzle 22. Preferably,the first and second seating surfaces 30 and 32 are co-axial; however,they need not be, provided that the transverse cross-sectional peripheryof the second seating portion is within the transverse cross-sectionalperiphery of the first seating portion.

The first seating surface 30 may be frustoconical, having a slight tapertowards its axis A in the direction toward the remote end 37 tofacilitate insertion of the nozzle 22 into the first pipette tip 25. Theinterior surface at the nozzle-mating end 38 of the first tip 25 and thefirst seating surface 30 are configured to sealingly mate together. Forexample, the large seating portion 32 may be shaped and dimensioned toprovide a leak resistant seal with a 5 mL disposable pipette tip such asa 5 mL tip by Macro Tips for Gilson™, Rainin™ and Pipetman™ Pipettorsmanufactured by USA Scientific.

In similar fashion to the first seating surface 30, the second seatingsurface 32 may be frustoconical, having a slight taper towards its axisA in the direction toward the remote end 37, which sealingly mates withthe interior surface at the nozzle-mating end 39 of the second tip 27.For example, the second seating portion 32 may be configured to providea leak resistant seal with a 1 mL disposable pipette tip such as a 1100μL level sensing tip manufactured by Qiagen™, or a 1100 μL tip forQiagen™ and Rosys™ robots manufactured by USA Scientific. A levelsensing tip is not necessary if the instrument is not able to senseliquid levels through the tip head, however tips designed for roboticsystems such as the Qiagen™ Biorobots™ have a narrow profile that isuseful for accessing fluid at the bottom of relatively full containerswithout causing the fluid to overflow, or from accessing fluid innarrow, deep containers.

The terms ‘leak resistant seal’ and ‘sealingly mate’, which are usedthroughout this document in connection with the seal between the pipettetip 23 and the nozzle 22 mean that a seal is provided that does notallow air to pass into the pipette tip such that fluid does notinadvertently drip from the tip; or a seal that, if it does allow air topass into the pipette tip, the rate at which the air passes into the tipis slow enough so that fluid does not inadvertently drip from the tip inthe time it takes to transfer the volume of fluid from one vessel toanother.

Referring to FIG. 4, a fluid passageway 40 extends through the nozzle22, and may include the first bore 42, a second bore 43 having adiameter smaller than the first bore 42, and a third bore 44 having adiameter smaller than the second bore 43. The first bore 42 may be usedfor connecting the nozzle 22 to the pipette head 20 (see FIG. 7). Forexample, the first bore 42 may be sized to frictionally engage bypress-fit the external surface 105 on the pipette head 20.

Reference is made to FIGS. 5 and 6. To acquire a pipette tip 23 for usein a fluid transfer operation, the nozzle 22 and the selected pipettetip 23 are brought into alignment such that the longitudinal axis A ofthe nozzle 22 is aligned centrally with the open end of the pipette tip23. The nozzle 22 is moved toward, and inserted into the pipette tip 23until the tip 23 is firmly seated on the appropriate seating portion 30or 32 to form a leak resistant seal between the nozzle 22 and thepipette tip 23. The terminal taper 36 serves to guide the pipette tipnozzle 22 into the tip 23 in the event that the nozzle 22 is notprecisely aligned with the nozzle-mating end 38 or 39 of the pipette tip23 during tip acquisition. If the nozzle 22 is being inserted into afirst tip 25, the tapered shoulder 34 serves to further guide the nozzle22 into the tip 25 if they are not precisely aligned.

The embodiment described herein is of a tip head with a nozzle that canaccommodate two sizes of pipette tips. However, based on the disclosureof the present invention, it will be appreciated by one skilled in theart that the nozzle of the present invention may be constructed withthree or more seating surfaces, to accommodate a corresponding number ofsizes of pipette tip 23.

In an alternative embodiment that is not shown, the first and secondseating surfaces on the nozzle may alternatively have other shapes thanfrustoconical. For example, the surfaces may be cylindrical. Inembodiments, wherein the first and second seating surfaces arecylindrical, they are preferably provided with ‘lead-in’ surfaces, whichmay be a conical or frustoconical shoulder at each of their leadingedges to facilitate insertion of the nozzle into a pipette tip. Thenozzle-mating ends of the pipette tips may correspondingly becylindrical, and may optionally be fitted with sealing members thereinfor sealingly mating with the seating surfaces.

The nozzle 22 may be made from a suitable stainless steel as will beappreciated by one skilled in the art.

Referring to FIG. 7, the pipette head 20 includes a reservoir system 111in accordance with another embodiment of the present invention. Thereservoir system 111 may include a first housing portion 110 and asecond housing portion 112, together forming a housing 107. Thereservoir system 111 also includes a fluid reservoir 100, which may beslideably mounted within the housing 107 and may be generallycylindrical in shape. The reservoir 100 has an abutment surface 101,which may be positioned proximate one end. The abutment surface 101 maybe frustoconical in shape, tapering to a smaller diameter in a downwarddirection. It is alternatively possible, however, for the abutmentsurface 101 to have another shape instead of being frustoconical. Forexample, the abutment surface 101 may extend in a plane that istransverse to a longitudinal axis Ar of the reservoir 100. The abutmentsurface 101 mates with a retainer surface 124 on the second housingportion 112 thereby assisting in retaining the reservoir 100 within thehousing 107.

The reservoir 100 further includes a shoulder 103 which faces away fromthe abutment surface 101, and which may be immediately adjacent theabutment surface 101. The shoulder 103 is discussed further below.

The reservoir system 111 further includes a connector surface 105 forconnecting with a pipette nozzle, such as nozzle 22, although othersuitable nozzles may be used instead of the nozzle 22. When a nozzle,such as nozzle 22 is connected to the pipette head 20, it should beconfigured so as not to interfere with the motion of the reservoir 100with respect to the housing 107, which will be described further below.

The reservoir 100 includes a fluid chamber 102, a pump-side port 104 anda pipette-side port 106. Regarding terms of spatial reference usedherein, the reservoir 100 in the illustrations should be regarded asbeing oriented along a vertical axis that is perpendicular to animagined horizontal surface. Accordingly, the pump side port 104 islocated at top or upper end 108 of the reservoir 100, and thepipette-side port 106 is located at bottom or lower end 109 of thereservoir 100.

The first housing portion 110 has an inner surface 116, and the secondhousing portion 112 has an inner surface 118. The housing portions 110and 112 may be connected together by any suitable means, such as by athreaded connection 114.

A slide surface 117 slidably receives the reservoir 100. The slidesurface 117 may be positioned in the first housing portion 110. The restof the inner surface 116 may be spaced from the reservoir 100 so thatthe slide surface 117 is the only portion of the inner surface 116 thatcontacts the reservoir 100.

The majority of the inner surface 118 is larger than the reservoir 100,and provides sufficient spacing from the reservoir to permit a spring120 to be positioned around the reservoir 100. The inner surface 118includes the retainer surface 124 which engages the abutment surface 101on the reservoir 100 to retain the reservoir 100 in the housing 107.

An internal shoulder 119 is positioned in the housing 107. The shoulder119 may be defined at the junction between the first and second housingportions 110 and 112.

The spring 120 may be a compression spring which is captured between theinternal shoulder 119 and the shoulder 103 on the reservoir 100. Thespring 120 thereby exerts a biasing force on the reservoir 100 drivingthe abutment surface 101 to seat against the retainer surface 124. Thespring 120 dampens the forces exerted upon the pipette nozzle 22 and thearm 12 overall as the nozzle 22 is inserted into a pipette tip 23, andfacilitates the sealing of the pipette tip 23 onto the nozzle 22. As therobot arm presses the nozzle onto the tip, the spring, which ispre-compressed to exert a force of at least 40 N, preferably 55 N,compresses further, such that the force of the nozzle on the tip doesnot vary greatly over several mm of vertical travel. In this example theforce applied by the nozzle on the tip increases approximately 1.5 N/mmof additional compression of the spring.

Referring to FIG. 9, the pipette-side port 106 communicates with passage40 of the pipette nozzle 22. Mounted within the pipette-side port 106and the passage 40 is a first conduit 128, which may be a tube having afirst end with a first opening 129 near the upper end 108 of the chamber102 and having a second end at the remote end 37 of the nozzle 22 orwhich may extend 1-2 mm beyond the end 37 of the nozzle 22. The firstopening 129 of the first conduit 128 is open and in fluid communicationwith the chamber 102. The first conduit 128 extends through the nozzleto its second end whereat it has a second opening 137 which may be flushwith the remote end 37 of the nozzle 22, or which may extend 1-2 mmbeyond the end 37 of the nozzle 22. The first conduit 128 provides fluidcommunication between the chamber 102 and the inside of a pipette tip 23when one is mounted on the nozzle 22.

Mounted within the pump-side port 104 is a second conduit 130, which maybe a tube, which extends into the fluid chamber 102 and has an end witha first opening 131 near the lower end of the chamber 102. The opening131 provides fluid communication between the second conduit 130 and thechamber 102. To facilitate the assembly of the tubes 128 and 130 withinthe chamber 102, the reservoir 100 may be made from two portions 143 and145 which are joined by means of a threaded connection 141. An O-ringseal 142 may be incorporated into the threaded connection to provide anairtight seal between the portions 143 and 145. The second conduit 130communicates fluidically with a pump (not shown) that provides thepressure differential required for drawing fluid into the pipette tip orexpelling fluid therefrom. The other end of the second conduit 130 maycommunicate with another conduit 133, which is attached to reservoir 100via a mounting screw 125. The threaded connector (ie. the mounting screw125), seals with the reservoir 100 by compressing an o-ring between thereservoir 100 and the connector 125.

Referring to FIG. 9, the reservoir 100 includes the pipette-side port106 which communicates with passage 40 of the pipette nozzle. Mountedwithin the pipette-side port 106 and the passage 40 is a first conduit128, which may be a tube, which extends from the remote end 37 of thenozzle 22 into the fluid chamber 102, having an end with a first opening129 near the upper end of the chamber 102. Accordingly, the firstconduit 128 is in fluid communication with the inside of a pipette tip23 when one is mounted on the nozzle 22. The first opening 129 of thefirst conduit 128 is open and in fluid communication with the chamber102. The first conduit 128 has another end which extends through thenozzle 22 and which has a second opening 137 which may be flush with theend 37 of the nozzle 22.

Mounted within the pump-side port 104 is a second conduit 130, which maybe a tube, which extends into the fluid chamber 102 and has an end witha first opening 131 near the lower end of the chamber 102. The opening131 provides fluid communication between the second conduit 130 and thechamber 102. To facilitate the assembly of the tubes 128 and 130 withinthe chamber 102, the reservoir 100 may be made from two portions 143 and145 which are joined by means of a threaded connection 141. An O-ringseal 142 may be incorporated into the threaded connection to provide anairtight seal between the portions 143 and 145. The other end of thesecond conduit 130 communicates fluidically with a pump (not shown) thatprovides the pressure differential required for drawing fluid into thepipette tip or expelling fluid therefrom. The other end of the secondconduit 130 may be positioned for example to communicate with anotherconduit 133 which is mounted to the reservoir 100 by means of a mountingscrew 125, which in turn communicates with the pump.

There are several suitable pumps that would be known to persons skilledin the art, such as, for example, model 3.6/120 or 3.6/265 manufacturedby DRD Diluter Corporation. Other pumps that would be suitable includesingle piston positive displacement pumps such as Series 3500 pumps fromScivex™ with 3.0 or 5.0 mL pump volume and shallow thread pitch. The DRDpump is a dual piston design which allows for accurate low and highvolume dispensing, with higher flow-rate high volume dispensing.

Reference is made to FIGS. 10 a and 10 b. In operation, the fluidchamber 102 contains a selected volume of hydraulic fluid 134. Thevolume of the chamber 102 should be selected such that the total volumeof hydraulic fluid 134 held in the chamber 102 and the conduits 128 and130 is greater than the maximum volume to be pipetted. In this way thepump will not draw air into its piston (or into the pumping mechanism ifnot a piston-type pump). Preferably, the volume in the chamber 102 andtubing 128 and 130 are selected based on the maximum desired fluidhandling volume so that there is less fluid wasted during priming whichis described below. For example, to handle a maximum volume of 5 mL, thepreferred volume of the chamber is and tubing is 6.7 mL.

In order to draw fluid into a pipette tip 23 that is mounted on thepipette nozzle 22, the pump (not shown) is made to apply suction to thesecond conduit 130 to aspirate a desired volume of hydraulic fluid 134from the chamber 102. The withdrawal of the fluid 134 from the chamber102 creates a negative pressure differential between the chamber 102 andthe pipette tip 23, and results in fluid 135 being drawn into thepipette tip 23 from a container 17 (see FIG. 1) until an equilibrium inpressure in the system is reached. To expel fluid 135 from the pipettetip 23, the pump is made to apply pressure to the second conduit 130which injects hydraulic fluid 134 into the chamber 102, creating apositive pressure differential between the chamber 102 and the pipettetip 23, causing the pipette tip 23 to expel fluid 135 until anequilibrium pressure is reached. The volume of hydraulic fluid 134 thatis withdrawn from or injected into the chamber 102 is proportional tothe volume of fluid 135 that is aspirated into or expelled from thepipette tip 23.

The fluidic system described above comprising tubing 128 and 130 and thereservoir 102 connects the nozzle 22 (FIG. 9 b) to the pump (not shown)and attains a known starting condition through a priming action duringstart-up, and periodic flushing action while performing processes. Theneed to prime and flush the fluidic system will be understood by thoseskilled in the art. The nozzle 22 (FIG. 9 b) does not hold a tip duringpriming and flushing actions. The priming action generally consists of aseries of steps that are repeated several times. A valve (not shown) tothe tubing 130 that connects the pump (not shown) to the pump hydraulicfluid reservoir (not shown) is opened and a valve (not shown) to thenozzle 22 (FIG. 9 b) is closed. The hydraulic fluid 134 is preferablysterile deionized water, but can be any other suitable fluid known tothose skilled in the art, such as saline solution. A selected volume isdrawn into the pump. The valve to the hydraulic fluid is then closed andthe valve to the nozzle 22 is opened, and the maximum volume ofhydraulic fluid is expelled. Usually three complete cycles of thesesteps are used to ensure that the complete volume of water in thefluidic system between the nozzle and the pump (not shown) is replacedand that most of the air is displaced from the system between the pumphydraulic fluid reservoir and the nozzle 22, including all of the tubing128 and 130, the reservoir 100 and the pump (not shown).

Generally, a flushing action is performed after the priming actiondescribed above, as well as periodically as needed, to put the system ata known fluidic starting condition. The flushing step consists ofdrawing a selected volume eg. 500 μL of hydraulic fluid 134 into thepump and then expelling this volume through the nozzle in the samemanner as for the flushing operation. The pump then slowly draws in a200 μL volume of air. This air volume provides a fluidic gap between thenozzle and the hydraulic fluid and serves to reduce the chance that thehydraulic fluid will be expelled into a pipette tip therebycontaminating the tip and potentially contaminating the fluid 135 thatthe tip aspirates during a fluid manipulation step. The air volume ispreferably small relative to the maximum desired pipetting volume toavoid a large compressible volume between the nozzle and pump.

By providing an indirect fluid connection between the pump (not shown)and the nozzle 22 by use of the reservoir system 102 of the presentinvention, the automated pipette machine 10 is able to handle a widerrange of volumes than would otherwise be possible, without having toutilize an extraordinary length of tubing as in devices of the priorart. Fluid handling robots that rely on a continuous length of tubing tohold the air volume displaced from a disposable tip during an aspirationstep have several other disadvantages relative to the present systemwith a reservoir. For example, in a long length of tubing there is anincreased chance that as the hydraulic fluid is drawn into the pump,there will be breaks at the air-hydraulic fluid interface resulting inthe formation of discrete bubbles between the main interface and thenozzle. When the pump initiates the dispensing step, these bubbles willbe ahead of the main interface and may be expelled from the nozzle 22,contaminating the tip 23 and potentially contaminating the fluid thatthe tip 23 aspirated, and hence the fluid volume into which the tip 23is dispensing. In a system with a reservoir 100, these bubbles willbreak in the chamber 102. The combination of relatively short lengths oftubing and the reservoir provide a relatively lower overall pressuredrop than a system of the prior art having a similar total internalvolume, that relies entirely on small-diameter tubing between the pumpand the tip for holding hydraulic fluid and air. Accordingly, thereduced pressure drop in turn reduces the risk of cavitation of the pumpat higher flow rates. Further, the system of the present invention canprovide higher flow rates for a given pump, or a similar flow rate toprior art systems using relatively lower-performance pumps, which maythus be less expensive, and which may consume less energy. Furthermore,since a selected flow rate can be achieved at a relatively lowerpressure drop than for systems of the prior art, the risk of leakageeither in or out of the system is reduced.

FIGS. 11-14 show selected components of the pipette machine 10 toillustrate the structure and operation of the tip ejector system 200 inaccordance with another embodiment of the present invention. The tipejector system 200 includes an ejector arm 204 which cooperates with thecarousel 14 and the arm 12 during the ejection of a tip 23 from thepipette nozzle 22.

A pipette tip carrier 220 holds one or more sizes of disposable pipettetips 23. For example, the carrier 220 shown in FIG. 11 has a pluralityof apertures 222 for holding first tips 25 and a plurality of apertures223 for holding second tips 27. The tip ejection system described andillustrated herein is adapted to be used with the dual-tip nozzle 22that is described above. However it will be understood that the tipejector system 200 may be used with other configurations of nozzles 22,such as, for example, with nozzles that are adapted to receive only onesize of tip.

During the operation of acquiring a pipette tip 23 for use in a fluidtransfer operation, the nozzle 22 and a pipette tip 23 are brought intoalignment by the rotation of the carousel 14 and/or the rotation of thearm 12 such that the nozzle 22 is aligned for insertion into thenozzle-mating end 38 or 39 of the pipette tip 23. The nozzle 22 is thenmoved toward and inserted into the pipette tip 23 until the tip 23 isfirmly seated on the appropriate seating surface—the first seatingsurface 30 (see FIG. 12 d), or the second seating surface 32 (see FIG.13 d)—so as to form a leak resistant seal between the nozzle 22 and thepipette tip 23. The nozzle 22 is then moved away from the carousel 14which withdraws the mounted pipette tip 23 from its tip compartment inthe tip carrier. The movement of the nozzle 22 may be in any suitabledirection, such as, for example, vertically, ie. in the z-direction.

The ejector arm 204 may engage the tips 23 during ejection in anysuitable way, while permitting the movement of the arm 12. For example,the ejector arm may have first and second open-ended slots 205 and 207.The first slot 205 has an end portion 206, which may be semi-circularand which is adapted to clear the outer diameter of the first seatingportion 30 of the nozzle 22 at all conditions of positional tolerancewhile being simultaneously small enough to interfere with the shoulder213 of a corresponding pipette tip 25. The second slot 207 has an endportion 208, which may be semi-circular and which is adapted to clearthe outer diameter of the small seating portion 32 of the nozzle at allconditions of positional tolerance while being simultaneously smallenough to interfere with the shoulder 215 of a corresponding pipette tip27. It will be apparent to persons skilled in the art that the slottedmember 204 may have more or fewer slots of different sizes to correspondwith the number and size of the pipette tips 23 being used.

The ejector arm 204 may extend in a generally horizontal plane. Theejector arm 204 is connected to a drive mechanism (not shown) andcontroller which control and drive its movement between first and secondpositions. The ejector system 200 may be configured to provide motion,eg. rotary motion, of the ejector arm 204 in a horizontal plane.Alternatively, in an embodiment that is not shown, the ejector system200 may be configured to provide linear motion to the ejector arm 204 ina horizontal plane. As another alternative, the ejector system 200 couldprovide motion to the ejector arm 204 along a path that is not along ahorizontal plane.

In the embodiment shown in FIG. 11, there is provided an elongatevertical member 202 which is connected to a drive motor or actuator (notshown) that causes the rotation of the vertical member 202 about itsaxis in response to signals received from the controller (not shown)that operates on programmed instructions. Precise movement and controlof the ejector arm 204 may be accomplished by any means known in theart.

The slots 205 and 207 on the ejector arm 204 are positioned such that,by the coordinated movement of the carousel 14 and the ejector arm 200,a selected slot 205 or 207 can be made to be in alignment with theselected tip compartment 222 or 223 on the carousel 14 wherein animaginary center of the semicircular end 206 or 208 of the slot 205 or207 intersects a central vertical axis of the tip compartment 222 or223, as illustrated in FIGS. 14 a and 14 b respectively. In a particularembodiment, this alignment can occur at the same time as the tipcompartment is positioned such that the tip head is able to lower a tipinto the compartment.

FIGS. 12 a, 12 b, 12 c and 12 d illustrate the ejection of a firstpipette tip 25 from the first seating surface 30 of the nozzle 22. FIGS.13 a, 13 b, 13 c and 13 d illustrate the ejection of a second pipette 27from the second seating surface 32 of the nozzle 22.

The mounted pipette tip 25 or 27 and a corresponding tip compartment(222 or 223) are brought into alignment by the rotation of the carousel14 and/or the rotation of the arm 12 such that the longitudinal axis ofthe tip is centrally aligned with the opening of the tip compartmentFIGS. 12 a and 13 a). The pipette tip 25 or 27 is then lowered partiallyinto the tip compartment 222 or 223 until the shoulder (213 or 215) isslightly below the horizontal plane of the slot (205 or 207) on theejector arm 204 that corresponds to the size of the pipette tip beingused (FIGS. 12 b and 13 b). The ejector arm 204 is rotated to swing thehorizontal member 224 toward the nozzle until the slot (205 or 207)surrounds the nozzle in the region just above the shoulder (213 or 215)of the pipette tip (25 or 27) (FIGS. 12 c and 13 c). The pipette head 20is moved vertically upward whereby the horizontal member 224 interfereswith the shoulder (213 or 215) of the pipette tip 25 or 27 and dislodgesit from the nozzle 22; the pipette tip 25 or 27 falls into the tipcompartment 222 or 223 (FIGS. 12 d and 13 d). The pipette head 20 isable to pick up another pipette tip 25 or 27 if suitable once theejector arm is withdrawn from the area above the carousel, including thepipette tip that was discharged if reuse of the tip 25 or 27 issuitable.

The pipette tips 25 and 27 have been described as including a shoulderwhich is engaged by the tip ejector arm of the present invention duringtip ejection. It is optionally possible for the tips to be made withshoulders that extend only partially or fractionally around thecircumference of the tips, while still functioning to engage the ejectorarm during tip ejection.

The described and illustrated embodiment of the tip ejector system 200is shown used in conjunction with a dual pipette tip nozzle. However,the present invention may be practiced in embodiments that accommodateother configurations of pipette heads and tip nozzles. For example, atip ejector system in accordance with the present invention may be usedwhere there are two independent tip heads each with a nozzle thataccommodates different sized pipette tips but that engages acorresponding notch in the ejector arm during a tip ejecting operation.Also, a tip ejector system in accordance with the present invention maybe used in conjunction with a single nozzle tip head by using, forexample, an ejector arm with one appropriately dimension slot, or inconjunction with a tip head that accommodates multiple pipette tips ofthe same size by using a stripping arm with a number of appropriatelydimensioned slots that correspond to the number of tips on the tip headand spaced appropriately on the ejector arm so as to engage the shoulderon each tip. Furthermore, the tip ejector system of the presentinvention may be used in conjunction with a tip head having nozzles thatare able to accommodate more than two different sized pipette tipswherein the ejector arm has appropriately sized and positioned notches.

Most automated pipetting robots have three axes of motion to allow thetip head to access the fluid in different containers in a given area.The tip ejector system 200 described herein is used with a θ-z-θ robotwhere the rotational (θ) and vertical (z) motion of a robot arm holdingthe tip head is combined with rotational (θ) motion of the carousel toallow the tip head to access a given point on the carousel. Because thetip stripping operations must occur on the carousel where the horizontalarc described by the rotation of end 37 of the tip nozzle intersects thehorizontal arcs described by the rotation of the tip stripping slots 205and 207, rotation of the carousel allows stripping actions to occur atpoints on circles concentric with the point of rotation of the carousel.However the tip ejector system 200 described herein could alternativelybe used with the more common x-y-z gantry style robot (e.g. BioMek FX™,Qiagen™ Biorobots™) where the tip head has one vertical and twoorthogonal horizontal axes of motion. For use with an x-y-z robot theejector arm could rotate as described. Alternatively however, theejector arm could be made to move linearly in, for example, a horizontalplane.

While the above description constitutes the preferred embodiments, itwill be appreciated that the present invention is susceptible tomodification and change without departing from the fair meaning of theaccompanying claims.

1. A tip ejector system for use on an automated pipette machine to ejecta pipette tip from a pipette nozzle on the machine, the tip ejectorsystem comprising: an arm that is rotatable in a horizontal planebetween a first position and a second position, wherein in the firstposition the arm is positioned to engage the tip during movement of thenozzle along a selected path and to prevent movement of the tip alongsaid selected path while permitting the nozzle to move along saidselected path, so that said movement of the nozzle along said selectedpath causes said nozzle and said tip to disengage from each other,wherein in the second position the arm is positioned to avoid engagementwith the tip during movement of the nozzle, wherein the arm defines aslot, and wherein the slot has a selected width that is sufficientlylarge to fit a first portion of the pipette nozzle and sufficientlysmall to prevent pass-through of at least one portion of the tip.
 2. Atip ejector as claimed in claim 1, wherein the slot is a first slot andsaid pipette tip is a first pipette tip, and wherein the arm has atleast a second slot, wherein the second slot has a different width thanthe first slot, wherein the second slot has a selected second width thatis sufficiently large to fit a second portion of the pipette nozzle andsufficiently small to prevent pass-through of the at least a portion ofa second tip.
 3. A tip ejector as claimed in claim 1, wherein theautomated pipette machine includes a carousel, wherein the carousel hasa plurality of pipette receptacles, wherein the first position of thearm is selectable based on the position of the receptacle into which thepipette tip is to be ejected.
 4. An automated pipette machine,comprising: A. a movable carousel having a plurality of pipettereceptacles; B. a movable pipette machine arm with a pipette nozzle, thepipette nozzle including: a body defining a passage there through; andat least two seating surfaces on the body, including a first seatingsurface and a second seating surface, wherein the first seating surfaceis configured to receive and sealingly mate with a first size of pipettetip in a manner such that the passage is in fluid communication with thefirst size of pipette tip, and wherein the second seating surface isconfigured to receive and sealingly mate with a second size of pipettetip in a manner such that the passage is in fluid communication with thesecond size of pipette tip; and C. a tip ejector system including: a tipejector arm that is movable between a first position and a secondposition, wherein in the first position the tip ejector arm ispositioned to engage the tip during movement of the nozzle along aselected path and to prevent movement of the tip along said selectedpath while permitting the nozzle to move along said selected path, sothat said movement of the nozzle along said selected path causes saidnozzle and said tip to disengage from each other, and wherein in thesecond position the tip ejector arm is positioned to avoid engagementwith the tip during movement of the nozzle.
 5. An automated pipettemachine as claimed in claim 4, wherein the tip ejector arm rotates in ahorizontal plane between the first and second positions.
 6. An automatedpipette machine as claimed in claim 5, wherein the tip ejector armdefines a slot, wherein the slot has a selected width that issufficiently large to fit the first seating surface of the pipettenozzle and sufficiently small to prevent pass-through of at least aportion of the tip.
 7. An automated pipette machine as claimed in claim6, wherein the slot is a first slot and said pipette tip is a firstpipette tip, and wherein the tip ejector arm has at least a second slot,wherein the second slot has a different width than the first slot,wherein the second slot has a selected second width that is sufficientlylarge to fit the second seating surface of the pipette nozzle andsufficiently small to prevent pass-through of the at least a portion ofa second tip.
 8. An automated pipette machine as claimed in claim 4,wherein the first position of the tip ejector arm is selectable based onthe position of the pipette receptacle into which the pipette tip is tobe ejected.